Epigenetics of Cocaine and Nicotine Addiction

This project characterizes DNA methylation and gene expression changes that occur in the human brain, specifically in neurons from the rostral striatum. Major advances from NIDA funded initiatives for noninvasive neuroimaging studies have made it possible to study neuroanatomical, neurochemical and functional changes in the human brain that contribute to the vulnerability to abuse drugs, together with the neurotoxic consequences of years of drug misuse. Animal models have been developed to explain the fundamental behavioral and biological mechanisms of addiction, including reward, tolerance and dependence. From these studies, we learned that cocaine abuse not only alters the epigenetic status of genes, but also induces particular epigenetic modifications depending on the frequency of the drug's administration. Certain genes are switched on by infrequent (short-term exposure) administration, while others are switched on only after chronic administration (addiction/dependence). Animal studies have also suggested that cocaine-seeking habits modeling chronic cocaine addiction in humans depend upon dopamine-dependent serial connectivity linking the ventral (nucleus accumbens) with the dorsal striatum (caudate nucleus). The primary goal of this study is to identify DNA methylation and gene expression changes that occur in the transition from recreational cocaine use to cocaine addiction. High throughput sequencing studies were designed to investigate unique postmortem human brain specimens from individuals that met criteria for cocaine dependence, as compared to unaffected age-matched controls.

Brain biospecimens were available from the University of Miami Brain Endowment BankTM, from a collection of phenotypically well-characterized postmortem tissues sampled from chronic cocaine abusers that came to autopsy. This biobank of postmortem brain specimens and annotated genomic data serve as a research resource to support NIDA's scientific mission.

• Study Design:
  • Case Set
• Study Type:
  • Case Set
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 380
• Subject Sample Telemetry Report (SSTR)

• BioProject
• BioSample
• MeSH

Inclusion Criteria:Cocaine Dependent Subjects (DSM-IV)

Age: 18 - 55 years
Gender: Males and Females
DSM-IV Cocaine Dependence
PMI < 24 h, pH > 6.0, RIN > 6.5
Negative serology
Positive toxicology for cocaine and metabolites (blood and brain) at the time of death
Smoking history and nicotine and cotinine measurements
Cause of death: cocaine intoxication due to cocaine alone or cocaine in combination with alcohol

Exclusion Criteria

Positive urine toxicology for illicit drugs opiate or methamphetamine, amphetamine, MDMA, PCP
CNS prescription drugs (opiates, antidepressants, antiepileptics, antipsychotics, benzodiazepines)
Active seizure disorder or history of serious head trauma
Gross or microscopic evidence of brain trauma or active disease (stroke or hemorrhage)
Positive serology HIV
History of schizophrenia or schizoaffective disorder
Cause of death: opiates or polydrug intoxication (opiates, methamphetamine or other illicit or licit drugs)
Manner of death: suicide, asphyxiation, drowning

The Smokescreen® Genotyping Array by BioRealm® was created with support of a NIDA SBIR contract. The chip consists of an Affymetrix backbone with over 800,000 SNPs. The chip covers 98% of common genetic variation in 1000 nominated addiction genes. The chip contains 296,000 markers from African, East Asian, and European populations giving 66% coverage for people of African Ancestry, 82% for people of East Asian Ancestry, and 91 % for people of European ancestry. In addition, 20,000 markers from expert nominations for genes posited to be associated with substance abuse and co-morbid disorders are also included on the chip. In addition, included in the array are more than 11,000 markers in the nicotine acetylcholine receptor gene clusters and nicotine metabolizing genes. There are greater than 16,000 markers for related co-morbidities and diseases.

The samples will be released separately by contributing investigators, with ultimately a total of approximately 50,000 targeted.

• Primary Phenotype: Cocaine-Related Disorders

• Principal Investigator
  • Deborah C. Mash, PhD. University of Miami, FL, USA.
• Funding Source
  • National Institutes of Health, Bethesda, MD, USA.